Bacteria hijack an immune signaling system to live safely in our guts

How do our bodies establish equilibrium between our immune systems and the …

Our immune system operates under the basic premise that "self" is different from "non-self." Its primary function lies in distinguishing between these entities, leaving the former alone while attacking the latter. Yet we now know that our guts are home to populations of bacterial cells so vast that they outnumber our own cells, and that these microbiota are essential to our own survival.

As a recent study in Nature Immunology notes, "An equilibrium is established between the microbiota and the immune system that is fundamental to intestinal homeostasis." How does the immune system achieve this equilibrium, neither overacting and attacking the symbiotic bacteria nor being lax and allowing pathogens to get through? It turns out that our gut bacteria manipulate the immune system to keep things from getting out of hand.

Like many stories of immune regulation, this one is a tale of many interleukins (ILs). Interleukins are a subset of cytokines, signaling molecules used by the immune system to control processes such as inflammation and the growth and differentiation of different classes of immune cells. IL-22 is known to be important in defense, both ridding the intestines of bacterial pathogens and protecting the colon from inflammation.

IL-22 is produced by the subset of T cells defined by their expression of IL-17, known as TH17 cells, as well as by innate lymphoid cells. Sawa et al. report that in the intestine, most of the IL-22 is produced by a specific subset of innate lymphoid cells that live there, and not TH17 cells.

Microbiota can repress this expression of IL-22 by inducing the expression of IL-25 in the epithelial cells lining the walls of the intestine. The researchers deduced this because IL-22 expression goes down in mice after weaning, when microbial colonization of the intestine dramatically increases. When adult mice were treated with antibiotics, IL-22 production went up again. IL-22 production also increased during inflammation.

Microbiota also induce the generation of TH17 cells and, even though these normally make IL-22, this induction further depresses its production. The TH17 ended up competing with the innate lymphoid cells for the same pool of regulatory cytokines; as a result, all of them got less and became less active.

These innate lymphoid cells thus play a critical role in maintaining intestinal homeostasis. They make IL-22, which induces the production of antibacterial peptides by the lining and protects the intestine from pathological inflammation. Symbiotic microbiota make a safe home by tamping down the production of IL-22 by inducing IL-25. The TH17 cells can contribute to this tamping down by competing for regulators. The authors conclude by stating that “this complex regulatory network demonstrates the subtle interaction between the microbiota and the various forces of the vertebrate immune system in maintaining intestinal homeostasis.”

The big picture is that we like having certain bacteria in our gut. In fact, vertebrates have co-evolved with the bacteria in their guts for hundreds of millions of years. The immune system and the gut microbial community have developed a peaceful coexistence that benefits both, if all goes well. We get the bacteria to digest many kinds of carbohydrates for which we don't have our own digestive enzymes. They also make certain nutrients for us (like vitamin K). And the ones we like occupy the environmental niche, keeping bad ones from moving in. In return, we give the desirable ones a stable environment, let them keep some of the food for themselves, and even pass them around the world. But how do we tolerate them in the gut, where they are beneficial to us, and yet respond vigorously against them in the wrong place? That's what the article is about, There is a finely tuned balance (certainly not yet all understood) that hold the immune response in check. In fact, there is communication and cooperation between the immune system and the bacteria. Very interesting to try to model.

I imagine the immune system in the gut is a bit more complicated; we need to make sure we don't fall into the trap of assuming that the entire mechanism is confined to the process defined here. In any case, the body has multiple layers of defense; beneficial flora have likely developed some way around all of these (or the body has learnt to tolerate), while "bad" bacteria would be unlikely to do so. Any that would might get purged when we end up worshipping the porcelain ring, or - worst case - kill the host. Both would probably represent a terminal end for that particular strain, thus providing highly selective pressure against its ongoing development.

If you'd like to see how your gut acts without the beneficial bacteria, just get sick in a way that requires huge doses of antibiotics. My experience has been that things go much... smoother with the good bacteria present.

"Just wait until the hacker bacterium arrives and it figures out how to sign its own code to run whatever it wants. Then we'll be in a world of shit. Quite possibly, literally"

There have been something like that already, but smaller, eg. "HIV virus"

That's not quite it; HIV attacks the actual T-cells for the immune system. We're talking about a virus that's dangerous that manipulates the immune system via this pathway. But I suppose if you can attack the immune system directly, that's less work.

Fascinating. If the number of bacteria outnumbers our own cells it probably means that fecal matter must contain a colossal amount of bacteria, dead and alive, and that the breaking down of food continues for days after we excrete it albeit by additional colonies of bacteria. In the wild, most mammals’ feces seem to disappear after a while. I’m not aware of any insect that feasts on them so if the decomposition is mostly done by microorganisms is it fair to assume (from an evolutionary point of view) that a good number of them were created in the gut?

I could not find answer here to question if (and how) our immune system attack bad bacteria in guts but leave good/symbiotic bacteria alone?

All it shows is evidence that good/symbiotic bacteria developed ways to suppress immune system. But that still leave few questions:1) even suppressed, remaining immune system still attack good/symbiotic bacteria in same way as it attacks bad bacteria? 2) because it is suppressed, immune system in guts is less effective to fight even bad bacteria than in other parts of body?

In other words, I expected "solution" to this problem to be in good bacteria adopting something to make our immune system treat it as our "own", not in suppressing our immune system.

I thought of dung beetles but it seems to me that, on the surface, the amount of excrement produced by animals far exceeds the population of dung beetles. From an evolutionary point of view, one would think that dung beetles would swarm the fields after they have been fertilized with manure. Since farming and agriculture is at least a hundred thousand years old, one would think that beetles would have become an essential farming accessory. Maybe it is and I’m just showing my ignorance.

Fascinating. If the number of bacteria outnumbers our own cells it probably means that fecal matter must contain a colossal amount of bacteria, dead and alive, and that the breaking down of food continues for days after we excrete it albeit by additional colonies of bacteria. In the wild, most mammals’ feces seem to disappear after a while. I’m not aware of any insect that feasts on them so if the decomposition is mostly done by microorganisms is it fair to assume (from an evolutionary point of view) that a good number of them were created in the gut?

Any organic material put in moist ground will decompose. Dirt contains a huge quantity and variety of fungi and bacteria.

Just wait until the hacker bacterium arrives and it figures out how to sign its own code to run whatever it wants. Then we'll be in a world of shit. Quite possibly, literally.

It would be against its interests to screw (and possibly kill off) the host. If it could figure out to always triumph over any hostile invading foreign species without affecting us it'd be a win-win situation.

Fascinating. If the number of bacteria outnumbers our own cells it probably means that fecal matter must contain a colossal amount of bacteria, dead and alive, and that the breaking down of food continues for days after we excrete it albeit by additional colonies of bacteria. In the wild, most mammals’ feces seem to disappear after a while. I’m not aware of any insect that feasts on them so if the decomposition is mostly done by microorganisms is it fair to assume (from an evolutionary point of view) that a good number of them were created in the gut?

Any organic material put in moist ground will decompose. Dirt contains a huge quantity and variety of fungi and bacteria.

The bacteria in the soil are missing in processed food and synthetic supplements. Would you make a case to incorporate a few grams of soil in our diet? Isn’t this how animals re-populate their intestinal fauna?

I could not find answer here to question if (and how) our immune system attack bad bacteria in guts but leave good/symbiotic bacteria alone?

All it shows is evidence that good/symbiotic bacteria developed ways to suppress immune system. But that still leave few questions:1) even suppressed, remaining immune system still attack good/symbiotic bacteria in same way as it attacks bad bacteria? 2) because it is suppressed, immune system in guts is less effective to fight even bad bacteria than in other parts of body?

In other words, I expected "solution" to this problem to be in good bacteria adopting something to make our immune system treat it as our "own", not in suppressing our immune system.

Fascinating. If the number of bacteria outnumbers our own cells it probably means that fecal matter must contain a colossal amount of bacteria, dead and alive, and that the breaking down of food continues for days after we excrete it albeit by additional colonies of bacteria. In the wild, most mammals’ feces seem to disappear after a while. I’m not aware of any insect that feasts on them so if the decomposition is mostly done by microorganisms is it fair to assume (from an evolutionary point of view) that a good number of them were created in the gut?

Any organic material put in moist ground will decompose. Dirt contains a huge quantity and variety of fungi and bacteria.

The bacteria in the soil are missing in processed food and synthetic supplements. Would you make a case to incorporate a few grams of soil in our diet? Isn’t this how animals re-populate their intestinal fauna?

sorry for quoting the whole thing but... yogurt is one way we replenish. also even pasteurized food isn't antiseptic and does contain some organisms. In addition we eat a great amount of dirt.. just by swallowing every minute. There are many vectors for re-population of gut bacteria, but some are going to be both more efficient and better overall for the host.